It is well established that memories are formed and stored through changes in synaptic transmission in specific brain circuits. Considerable evidence points to the amygdala, and specifically its lateral nucleus (LA), as a key site of synaptic plasticity underlying Pavlovian fear conditioning, a leading model for studying the neurobiology of emotional memory. In fear conditioning, subjects are exposed to an emotionally neutral conditioned stimulus (CS) and an aversive unconditioned stimulus (US). Most progress has been made using an auditory CS paired with footshock as a US. In so-called auditory fear conditioning the convergence of the CS and US in the LA is believed to be necessary for conditioning to take place. However, the degree of synaptic plasticity taking place in the amygdala is thought to be regulated or modulated by neurochemicals, levels of which can strengthen or weaken the memory the is formed. One such modulator is norepinephrine (NE), which is released widely in the brain in situations involving attention, alertness, stress, or emotional arousal. NE is also known to play a key role in fear and anxiety disorders. In spite of its importance in fear and anxiety disorders, and its presumed role in memory formation and storage, relatively little is known about the contribution of NE in the LA to fear conditioning. The reason for this is two-fold. First, many previous studies of aversive learning have used behavioral paradigms that are poorly understood at the neural circuit level. Second, in spite of the fact that fear conditioning is well understood at the neural circuit level, most studies of the role of NE in fear conditioning have manipulated NE systemically rather than in the LA itself. The overall goal of this grant is to elucidate the contribution of NE to fear conditioning. The specific aims are to: answer these questions: (1) What is the contribution of NE to initial memory formation in conditioned fear? (2) Is the contribution of NE to initial fear memory formation distinct from its role in reconsolidation and extinction? (3) What are the downstream signaling cascades that are activated by NE in the LA during acquisition/consolidation vs. reconsolidation and extinction. (4) Is the locus coeruleus (LC) the source of NE in the LA that modulates acquisition and amygdala plasticity, and are the effects due to NE release induced by the aversive US. New evidence suggests that NE plays an especially important role in initial memory formation during the acquisition of fear conditioning. While activation of one set of NE receptors appears to facilitate learning, another set constrains the acquisition process. Because reconsolidation and extinction also have important clinical implications, results of studies of these phases will be compared to results from acquisition. These studies and results should give new insights into the contribution of NE in the amygdala to fear conditioning, and to understanding and treating disorders involving fear and anxiety. PUBLIC HEALTH RELEVANCE: Pavlovian fear conditioning is a leading model for studying the neurobiology of learning and memory and of disorders of fear and anxiety. In spite of the importance of norepinephrine (NE) to fear and anxiety disorders, and its presumed role in memory formation and storage, relatively little is known about the contribution of NE in the amygdala to fear conditioning.